Discussion
This series of patients illustrates both the promise and limitation of
MEK inhibition with trametinib monotherapy for LCH. Specifically,
patient 3 with MAP2K1 deletion and systemic LCH in the newborn
period showed a complete and durable response to trametinib and is
thriving with no active disease. On the other hand, patient 2 withBRAF deletion has had only a partial response to full dose
trametinib.
As suggested by Allen et al., there is a significant difference between
infants with isolated cutaneous LCH and infants who develop progressive,
life-threatening disease as patient 3. 1 The misguided
myeloid differentiation model proposed by Allen et al. would suggest
that patient 3 developed MAP2K1 deletion early in fetal life,
possibly in the yolk-sac progenitors or fetal liver
monocytes.1
The misguided myeloid differentiation model also suggests that the
origin of neurodegenerative LCH disease is from a hematopoietic cell
clone. 1 Whether this is true only for BRAFp.V600E mutation or other MAPK pathway variants remains to be seen.7,8 So far none of our patients have shown
neurodegenerative changes. McClain et al demonstrated BRAFp.V600E in peripheral mononuclear cells in patients with
neurodegenerative LCH. 8 We did not have the capacity
to evaluate the presence of the variants reported here in the peripheral
blood of our patients.
Though most patients with pulmonary LCH are adults with a smoking
history, our patients are younger (2 months – 18 years) with no smoking
history. 4 Jouenne et al., in a large adult LCH group,
noted the BRAF N486_P490del as the second most common variant
after BRAF V600E mutation. This was especially seen in
association with lung disease. 2
The dose and length of therapy of trametinib needed to inhibit the MAPK
pathway in LCH is not established. A retrospective study of 21 pediatric
LCH patients with MAPK pathway somatic mutation (BRAF p.V600E, n
= 20; MAP2K1c .293_310del, n = 1) who received MAPK pathway
inhibitors after failure of at least 1 prior therapy was recently
reported by the NACHO-LIBRE Study Group. 9 They
reported 86% response rate to therapy, and 6 patients in that group
received trametinib either in combination with BRAF inhibitors or alone.
The dose of trametinib in that report ranges from 0.0125-0.018 mg/kg or
reported as 1 mg or 2 mg daily. Patient 21 in that report had an
identical MAP2K1 deletion to our patient number 3. That patient
had brief response to trametinib for 2 months before suffering
progressive disease. 9 In contrast, our patient 3 had
remarkable response to trametinib daily lasting almost 2 years. Lee et
al. described a 36 year old female with similar BRAF p.N486_P490
deletion to our patients 1 and 2 who had a remarkable response to
trametinib within 5 days including PET/CT negativity after 4 months and
elimination of seizures within weeks. 5 The dose of
trametinib was not reported. Notably, our patient 2 had partial response
of lung disease on monotherapy with trametinib 2 mg daily.
Diamond et al. report that the MEK1/2 inhibitor cobimetinib (60 mg daily
for 21 days of a 28-day cycle) resulted in remarkable response rate
(89%) among adults with histiocytic disorders. 10 In
that report a patient with LCH and BRAF N486_P490del did seem to
have a complete response lasting 2 years, as did some of the patients
with MAP2K1 mutations. It is certainly possible that cobimetinib
is a better MEK inhibitor for LCH
In summary, 3 LCH patients are currently receiving monotherapy with
trametinib for systemic LCH. Two have BRAF p.N486_P490del and
one has MAP2K1 p.K57_G61del. These patients are tolerating
therapy with low grade skin toxicity and tolerable elevations in CPK
levels. Two (patients 1 & 3) are maintaining non-active disease
(follow-up 18-22 months) and one (patient 2) who had partial response is
stable with active disease (follow-up 12 months).